Leucine Rich Repeat (LRR) proteins are pivotal to many biological processes including innate immunity, but little is known about their role in adaptive immunity. A patient with recurrent infections, agammaglobulinemia, and absence of circulating B cells, but normal numbers of T cells, was found to carry a truncated LRRC8 (LRR Containing 8) cell surface receptor (7). A breakpoint between exons 3 and 4 due to a balanced translocation resulted in a truncated LRRC8?91/+35 protein in which the 91 C-terminal a.a. of the extra-cellular domain were replaced by 35 a.a. encoded by read though intron 3. Mouse CD34+ progenitors that express LRRC8?91/+35 failed to reconstitute the B cell compartment in irradiated recipients. Our preliminary data show that LRRC8-/- mice have increased mortality, stunted growth and abnormalities in a number of tissues. Thymic development was severely impaired with a major block between DN2 and DN3 stage and peripheral T cells failed to proliferate or secrete IL-2 in response to anti-CD3. We postulate that LRRC8 activates a pathway, e.g. Notch1 dependent signal transduction, that promotes T cell development, but shuts off B cell development. We will test the hypothesis that LRRC8 is critical for T cell development and function in a T cell autonomous fashion. We will also test the hypothesis that the deletion of 91 a.a. from or/and addition of 35 a.a to the EC domain of LRRC8 results in constitutive signaling by the mutant, which dominantly inhibits B cell development. We will 1. Test the hypothesis that LRRC8 is critical for T cell development in LRRC8-/- mice by performing detailed phenotypic characterization of T cells and thymic epithelial cells (TECs) in LRRC8-/- mice. 2. Test the hypothesis that LRRC8-/- T cells have an intrinsic defect in development and function. We will assess the developmental potential of LRRC8-/- thymocyte progenitors, examine if constitutively active Notch1 rescues the LRRC8-/- T cell maturation block, analyze the ability of LRRC8-/- TECs to support T cell development and determine the effect of conditional ablation of LRRC8 at defined stages of T cell maturation on T cell development and function. 3. Test the hypothesis that LRRC8-/- T cells have an intrinsic defect in development and function. We will compare the effect of LRRC8?91/+35 LRRC8?91 and LRRC8+35 mutants on cell signaling and on T and B cell development from BM progenitors, and we will analyze lymphocyte development and function in LRRC8?91/+35 knock-in mice. The results of these studies should enhance our understanding of the role of LRRC8 in normal immune function and the mechanisms of agammaglobulinemia in the patient with the LRCC8 mutant. These results will have important implications for primary immunedeficiencies, host defense autoimmunity and allergy.